GLI3:c.2880del导致的多指(趾)家系分析  

Analysis of a Chinese pedigree with polydactyly caused by GLI3:c.2880del

作　　者：文龙 刘福云[1] 段世超 许红恩 夏冰[1] 董延召[1] 程文哲 胡伟明[1] 冯国明[1] 张晴 Wen Long;Liu Fuyun;Duan Shichao;Xu Hongen;Xia Bing;Dong Yanzhao;Cheng Wenzhe;Hu Weiming;Feng Guoming;Zhang Qing(Department of Pediatric Orthopedics,Third Affiliated Hospital,Zhengzhou University,Zhengzhou 450052,China;Henan Provincial People's Hospital,Zhengzhou 450003,China;Precision Medicine Center,Academy of Medical Sciences,Zhengzhou University,Zhengzhou 450052,China;Henan Children's Hospital,Zhengzhou 450018,China)

机构地区：[1]郑州大学第三附属医院小儿骨科,郑州450052 [2]河南省人民医院,河南省立眼科医院青光眼中心,郑州450003 [3]郑州大学医学科学院精准医学研究中心,郑州450052 [4]河南省儿童医院外科监护室,郑州450018

出　　处：《中华小儿外科杂志》2023年第5期427-433,共7页Chinese Journal of Pediatric Surgery

基　　金：国家自然科学基金青年科学基金项目(No.32100543)。

摘　　要：目的探讨一个多指(趾)畸形家系潜在的致病基因及机制。方法收集多指(趾)家系5代11人的临床资料及外周血,全外显子测序,Sanger测序进行验证,确定突变位点。构建重组质粒,在293T细胞中进行外源表达,进行免疫印迹实验和免疫共沉淀实验确定突变蛋白分子量及融合抑制因子(suppressor of fused,SUFU)相互作用情况。结果先证者及其外曾外祖母、外祖母、母亲、舅舅均存在NM_000168.6(GLI3):[c.2880del,p.(Asp962MetfsTer41)]移码突变,正常成员未见异常。其表达一个分子量约为130 kDa截短的突变体,与SUFU的相互作用显著降低,音速刺猬(sonic hedgehog signaling,SHH)信号通路激活强度受限。根据美国医学遗传学和与基因组学学会遗传变异分类标准与指南评级为致病变异。结论GLI3:c.2880del突变是家系中多指(趾)的致病因,GLI3基因突变谱进一步丰富。Objective To explore the potential pathogenic genes and mechanisms of a family of polydactyly.Methods Clinical data and peripheral blood samples of 11 polydactyly families from 5 generations were collected and pathogenic variants identified by whole exome sequencing and verified by Sanger sequencing.The recombinant plasmid was constructed and its exogenous expression examined by immunoblotting and immunoprecipitation in 293T cells.The molecular quality of mutant proteins and the interaction of SUFU were analyzed.Results The results of phenotypic and genetic sequencing showed that there were five patients including proband and his great-grandmother,grandmother,mother and uncle,with frame-shift mutation c.2880del[p.(Asp962Metfs41Ter)]in GLI3 gene.The same variant was not detected in family members with normal phenotypes.According to the ACMG guidelines,this variant was classified as pathogenic.It decoded a truncated mutant with a molecular weight of about 130 kDa and its interaction with SUFU declined markedly with limited activation intensity of the Sonic Hedgehog signaling pathway.Conclusions As the causative factor of polydactyly in this family,GLI3:c.2880del further enriches the mutation spectrum of GLI3 gene and provides new insights of the SHH pathway and molecular mechanisms related to polydactyly.

关 键 词：多指(趾)畸形 GLI3移码突变 全外显子组测序 SHH信号通路 

分 类 号：R726.8[医药卫生—儿科]